Enyne and dienyne metathesis reactions in b-carbolines

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2 Tetrahedron Letters Tetrahedron Letters 46 (2005) Enyne and dienyne metathesis reactions in b-carbolines Álvaro González-Gómez, Gema Domínguez and Javier Pérez Castells * Departamento de Química, Facultad de Farmacia, Universidad San Pablo-CEU, Urb. Montepríncipe, Boadilla del Monte, Madrid, Spain eceived 24 June 2005; revised 27 July 2005; accepted 27 July 2005 Available online 6 September 2005 Abstract ew indolic enynes and dienynes, based on the b-carboline system, give metathesis products with ruthenium catalysts. The synthesis of the starting materials is readily achieved from tryptamine. The tuning up of the conditions for the metathesis is discussed. Cascade metathesis gives an oxidized pentacyclic product. Ó 2005 Elsevier Ltd. All rights reserved. The enyne metathesis reaction 1 is completely atom economical and formally implies the formation of a carbon carbon bond and the migration of the alkylidene part onto the alkyne carbon, to form a diene. In recent years, there has been great interest in intramolecular enyne metathesis 2 especially with regard to further transformations of the resulting conjugated dienes. Thus, domino transformations, including tandem CM of dienynes, have lead to synthetic applications in the field of polycycle construction and natural product syntheses. Enynes connected through an aromatic ring are interesting substrates that have found scarce use in this chemistry. We have used benzenic and indolic enynes to construct complex polycycles. 4 In this paper, we describe the first use of b-carboline derived enynes and dienynes in metathesis processes involving tandem metathesis reactions. This new approach is a powerful entry into polycyclic structures related to alkaloids containing the b-carboline unit such as those depicted in Figure 1. The synthesis of the starting enynes was accomplished from tryptamine. The reaction of tryptamine with ethylformate gives formamide 1 which, when treated with a and allyl bromide gives a mixture of monoallyl derivatives 2 and and diallylcompound 4. With a careful selection of the reaction conditions mono- or diallyl Keywords: Enynes; b-carboline; Metathesis; Cascade reactions; uthenium. * Corresponding author. Tel.: ; fax: ; jpercas@ceu.es O MeOOC Vincamine Arborescidine B C C Figure 1. Some b-carboline alkaloids. O C omoeburnane products can be made selectively (Scheme 1). Thus, excess of base and allyl bromide gave 4 as the only reaction product in 65% yield, while the use of 1 equiv of base and 2 equiv of allyl bromide gave a 2:1 mixture of 2 and which was separated by column chromatography, yielding pure 2 (64%) and (0%). Compound was protected on the indole nitrogen with tosyl chloride using a as the base, giving 5 in 80% yield. Compound 2 was cyclized using the Bischler apieralski reaction, giving the corresponding 9-allyldihydro-bcarboline which was reacted with an alkynylmagnesium bromide and protected, to afford the desired enynes 6a,b. Best yields were achieved when isolating the intermediate cyclic imine (Scheme 2a). On the other hand, compounds 4 and 5, were reacted with PO and the MeOOC Geissoschizine O /$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi: /j.tetlet

3 7268 Á. González-Gómez et al. / Tetrahedron Letters 46 (2005) a p- CO a 1 2 Prod. Yield corresponding Grignard reagent in a Ôone-potÕ fashion, affording 7 and 8a,b, respectively, in good yields (Scheme 2c and d). In this approach the synthesis of 8a,b started from which was a minor product obtained in the alkylation of 1. As the yield of compound was low, an alternative synthesis of 8a,b was addressed. Thus, we transformed quantitatively formamide 1 into the corresponding dihydro-b-carboline which was protected as the tosyl derivative, using in this case Cs 2 CO /K 2 CO as the base. The reaction with the appropriate alkynylmagnesium bromide yielded 9a,b in 52 59% yield from 1 (Scheme 2b). Subsequent allylation of these intermediates in position 2 gave 8a,b. The global yield of this route from 1 to the enynes 8a,b is 42% and 49%, respectively. We accomplished next, the metathesis reaction of these starting compounds. The reaction of enyne 6a was used as a model and was reacted with catalysts A, B and C under different reaction conditions (Scheme ). While catalyst A did not give any conversion (entry 1), both complexes B and C led to the desired diene product with similar yields, toluene being a better solvent % 0% 65% 80% CO 2 Conditions a 1:1:2 1:1:2 1:5:5 a Proportion of indole:base:allylbromide. Scheme 1. Synthesis of enyne precursors. than dichloromethane (entries 2 and ). All reactions were carried out at room temperature, as extensive decomposition of the starting material occurred when operating at an elevated temperature. We used a 10 mol% catalyst because we observed a significant decrease in yield when using only 5% of catalyst (entry 4). This point may be surprising as it is thought that complex B generates small amounts of 14e active species that give a high number of catalytic cycles. 5 Our reactions were at that point very slow and needed days to complete. We have monitorized the CM of 6a by 1 M which indicated the progressive conversion of the starting material into the diene. 6 In this context, the need for such a high amount of catalyst might be due to its partial decomposition. We have observed similar yields when adding the catalysts in portions every 12 h (% at the beginning and 1% additional every 12 h, completing 8%). We used 10 mol% of complex C, yielding 55% of although this reaction needed 6 days to complete (entry 5). In view of these results, cheaper complex B was used for the rest of the metathesis reactions. Our results improved remarkably when performing the reaction under an ethylene atmosphere (entry 6). 7 Ethylene is known to have a beneficial effect in metathesis reactions. 8 This conditions allowed the synthesis of in only h, using 5% of catalysts and in 95% yield. In the same way compound 6b was readily transformed into diene 10b. The use of ethylene allowed raising the yield to 85% (Scheme, entries 7 and 8). We also used these reaction conditions to carry out the metathesis reactions of 8a,b. These substrates gave the corresponding dienes 11 in good yield along with small amounts of an oxidized pyrrole 12. This ability to oxidize the reaction product is a known non-metathetic behaviour of ruthenium catalysts and it is particularly observed with complexes of type B (Scheme 4). 9 1, 2 (a) 6a-b 1) Mg BF *Et 2 O 2) a, p- Z = =, 58% = Me, 56% PO Z 1) Cs 2 CO /K 2 CO p- 2) Mg BF *Et 2 O Z = =, 52% = Me, 59% 81-8% 9a-b a, (b) CO (c) 1) PO 2) Mg Z = Z 75% 7 4, 5 1) PO 2) Mg Z = =, 67% = Me, 55% 8a-b (d) Scheme 2. Synthesis of starting enynes and dienynes.

4 Á. González-Gómez et al. / Tetrahedron Letters 46 (2005) Cat toluene, T 6a-b Mes PCy Mes Mes Ph u Ph u u PCy PCy O A B C Mes o Me Me -b Cat. A, 10% C, 10% Solv. DCM DCM Time 6d h a h a Prod. Yield(%) 10b 10b a Performed under a 1 atm of ethylene. Scheme. Metathesis reaction and tandem metathesis-diels Alder reaction of compounds 6a,b. Cat B, 8a-b 10% 11a, 62% 11b, 51% + 12a, 9% 12b, traces found no improvement by working under an ethylene atmosphere. 10 In conclusion, we show here the first enyne metathesis reactions in b-carbolines leading to polycyclic systems related to alkaloids. The synthesis of natural products using this methodology is currently underway. 1, not detected Cat., % A, 10% B, 6% a C, 6% a a 2 mol% added every 24 h. 7 Time Temp. Yield r.t. - r.t. 15% 80 o C 45% 80 o C 67% Finally, we present the first example of a tandem metathesis reaction on a b-carboline derivative. When reacting compound 7 under the above conditions we isolated in low yield a new pentacyclic structure whose analytical and spectroscopical data corresponded to compound 15. The cascade metathesis of compound 7 starts by reaction of one of the double bonds with the ruthenium carbene. The formation of 15 implies the coordination of the ruthenium first with the allyl group in position 9 of the starting material to give 14 which is oxidized under the reaction medium to 15. eaction with the allyl group in first would have produced 1 which was not detected in any of the reactions. In addition, raising the reaction temperature to 80 C gave better yields of 15. Thus, we switched to catalyst C, a more stable complex towards heat, and 2% catalyst was added to the reaction every 24 h during days. In this case we 15 14, not detected Scheme 4. Metathesis of 8a,b and cascade metathesis of 7. Acknowledgements The authors are grateful to the DGES (MEC-Spain, Grant BQU ), the Universidad San Pablo- CEU (Grant 07/0) for financial support. A.G.-G. acknowledges the Spanish MEC for a pre-doctoral fellowship. Supplementary data Supplementary data associated with this article can be found, in the online version at doi: /j.tetlet Experimental procedures and full spectroscopical data for all new compounds. eferences and notes 1. ecent reviews: (a) Giessert, A.; Diver, S. T. Chem. ev. 2004, 194, 117; (b) Mori, M. Ene yne Metathesis. In andbook of Metathesis; Grubbs,.., Ed.; Wiley-VC: Weinheim, 200; Vol. 2, p 176; (c) Poulsen, C. S.; Madsen,. Synthesis 200, 1; (d) Trnka, T. M.; Grubbs,.. Acc. Chem. es. 2001, 4, 18; (e) Fürstner, A. Angew. Chem., Int. Ed. 2000, 9, 012; (f) Maier, M. E. Angew. Chem., Int. Ed. 2000, 9, 207; (g) Grubbs,..; Chang, S. Tetrahedron 1998, 54, See, for recent examples: (a) Barrett, A. G. M.; ennessy, A. J.; Vezouet,. L.; Procopiou, P. A.; Seale, P. W.; Stefaniak, S.; Upton,. J.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2004, 69, 1028; (b) Mori, M.; Tomita, T.; Kita, Y.; Kitamura, T. Tetrahedron Lett. 2004, 45, 497; (c) enneman, J. B.; Martin, S. F. Org. Lett. 2004, 6, 129.

5 7270 Á. González-Gómez et al. / Tetrahedron Letters 46 (2005) ecent tandem dienyne metathesis examples: (a) García- Fandiño,.; Codesido, E. M.; Sobarzo-Sánchez, E.; Castedo, L.; Granja, J.. Org. Lett. 2004, 6, 19; (b) onda, T.; amiki,.; Kaneda, K.; Mizutani,. Org. Lett. 2004, 6, 87; (c) Fukumoto,.; Esumi, T.; Ishihara, J.; atakeyama, S. Tetrahedron Lett. 200, 44, 8047; (d) Boyer, F.-D.; anna, I.; icard, L. Org. Lett. 2001,, 095; (e) Choi, T.-L.; Grubbs,.. Chem. Commun. 2001, 2648; (f) Furstner, A.; Liebl, M.; ill, A. F.; Wilton- Ely, J. D. E. T. Chem. Commun. 1999, 601; (g) Zuercher, W. J.; Scholl, M.; Grubbs,.. J. Org. Chem. 1998, 6, 4291; (h) Kim, S.-.; Zuercher, W. J.; Bowden,. B.; Grubbs,.. J. Org. Chem. 1996, 61, osillo, M.; Domínguez, G.; Casarrubios, L.; Amador, U.; Pérez-Castells, J. J. Org. Chem. 2004, 69, See: (a) Sanford, M. S.; Love, J. A.; Grubbs,.. J. Am. Chem. Soc. 2001, 12, 654; (b) Sanford, M. S.; Ulman, M.; Grubbs,.. J. Am. Chem. Soc. 2001, 12, 749; (c) Aagaard, O. M.; Meier,. J.; Buda, F. J. Am. Chem. Soc. 1998, 120, An aliquot was taken from the reaction every 12 h, and after workup the crude was analyzed by 1 M showing progressive conversion of 6a into. 7. Experimental procedure for the synthesis of is as follows: To a 0.01 M solution of 6a (0.200 g, mmol) in anhydrous toluene, g (0.026 mmol) of Grubbs catalysts B was added and the resulting mixture was stirred at room temperature under a ethylene atmosphere for h. The reaction mixture was filtered off through a Celite pad and washed with toluene. The solvent was removed under reduced pressure and purified by column chromatography (hexane EtOAc, 9:1) giving pure (0.190 g, 95%) as yellow oil. 1 M (C 6 D 6,60 C) d (ppm): 1.76 (s, ), (m, 2), (m, 4), 5.11 (d, 1, J = 12.1 z), 5.48 (d, 1, J = 17.0 z), 5.68 (br s, 1), 6.0 (s, 1), 6.59 (d, 2, J = 8.2 z), 6.97 (d, 1, J = 7.7 z), (m, ), 7.24 (d, 1, J = 7.7 z), 7.62 (d, 2, J = 8.2 z). 1 C M (C 6 D 6, 60 C) d (ppm): 20., 21.0, 42.9, 46.8, 5.1, 106.1, 109.5, 115.4, 118.8, 119.9, 120.2, 121.6, 127., 128.4, 129.5, 129.9, 11.5, 14.5, 17.7, 19.1, I (K) m 1600, 140, 1160 cm 1. MS (ESI) m/z 91 (M+). Anal. Calcd for C O 2 S: C, 70.74;, 5.68;, Found: C, 70.99;, 5.89;, For other examples of the beneficial effect of ethylene see: (a) Mori, M.; Kuzuba, Y.; Kitamura, T.; Sato, Y. Org. Lett. 2002, 4, 855; (b) Saito,.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, Alcaide, B.; Almendros, P. Chem. Eur. J. 200, 9, Synthesis of 15: to a solution of 7 (0.150 g, 0.54 mmol) in anhydrous toluene (0 ml), 7 mg (0.011 mmol) of Grubbs C complex were added every 24 h during days while stirring at 80 C. The reaction mixture was filtered off through a Celite pad and washed with dry toluene (20 ml). The solvent was removed under reduced pressure and the residue purified by column chromatography (hexane EtOAc 49:1) giving 15 (0.101 g, 67%) as a yellow oil. 1 M (CD ) d (ppm):.16 (t, 2, J = 6.8 z), 4.22 (t, 2, J = 6.8 z), 4.82 (d, 2, J = 5.5 z), (m, 1), 6.14 (d, 1, J = 2.7 z), 6.65 (d, 1, J = 11.0 z), 6.70 (d, 1, J = 2.7 z), 7.11 (td, 1, J 1 = 7.7 z, J 2 = 1.1 z), 7.18 (td, 1, J 1 = 8.2 z, J 2 = 1.1 z), 7.4 (d, 1, J = 8.2 z), 7.51 (d, 1, J = 7.7 z). 1 C M (CD ) d (ppm): 21.4, 44.0, 45.2, 10.0, 107.4, 109., 116.1, 116.5, 117.8, 119.6, 121.0, 121.7, 127.5, 127.6, 128., 10.0, I (neat) m 1620, 1600 cm 1. MS (APCI), m/z: 247 [M+] +. Anal. Calcd for C :C, 82.90;, 5.7;, Found: C, 82,72;, 5.67;,

Anomalous metathesis reactions of 3,4-disubstituted indoles

Anomalous metathesis reactions of 3,4-disubstituted indoles Leticia Pérez-Serrano, Gema Domínguez, and Javier Pérez-Castells* Departamento de Química, Facultad de Ciencias Experimentales y de la Salud.